The Ontario Familial Colorectal Cancer Registry (OFCCR) is a productive member of the multinational six site Colon Cooperative Family Registries (Colon CFR). During Phases I and II (1997-2007), the OFCCR registered population based subjects, with family history data, epidemiologic risk factor data, dietary data, and biospecimens (blood, serum, tumor blocks) for over 4,800 incident colorectal cancer (CRC) cases, their 4,000 relatives, as well as similar data for over 1,900 controls from the province of Ontario, Canada. The OFCCR has contributed approximately one-quarter of all CFR cases, and half the CFR-wide population controls. The OFCCR biospecimen repository (BSR) at Mount Sinai Hospital (MSH) in Toronto maintains and distributes to the scientific community genomic germline DMA from OFCCR cases and controls, all of which have been EBV transformed to protect this valuable resource. During Phase II, the OFCCR recruited additional high risk families from the clinic-based Familial Gastrointestinal Cancer Registry at MSH;75 germline mismatch repair (MMR) gene mutation carriers and their relatives are now available for penetrance, epidemiologic, chemoprevention, psychosocial, and other research aimed at understanding familial and sporadic CRC. The OFCCR also contributed to the CFR, over 200 fresh frozen tumor samples, with annotated family history, epidemiologic and clinicopathologic data. Other unique contributions of the OFCCR to the Colon CFR include;germline MYH mutation testing of all Colon CFR cases and controls and the first genome wide association study in CRC that identified 8q24 SNPs that predict CRC susceptibility. In the current application (Phase III), the OFCCR proposes to continue as an active registry of the Colon CFR with the following Specific Aims: 1) expanding OFCCR families with MMR gene mutations, 2) recruiting additional high risk families from across Canada, 3) maintaining contact and follow-up of over 5,000 participants, 4) obtaining clinicopathologic and first treatment data on Phase I, II and III cases, 5) collaborating with the Colon CFR in molecular characterization of about 2,900 OFCCR cases (OFCCR will continue to test Colon CFR cases for MYH mutations), 6) adding to, and maintaining the OFCCR BSR and coordinating future efforts with the Colon CFR Central Repository, 7) maintaining the OFCCR bioinformatics core and coordinating efforts with RTI, the Informatics Center for the Colon CFR, 8) maintaining the OFCCR administrative core and contributing to the continued administrative efforts of the Colon CFR. The Colon CFR is the largest resource of its kind worldwide. Public health contributions of the OFCCR and the Colon CFR in general are far reaching including;providing a better understanding of susceptibility to CRC, identifying novel genetic markers of this disease, characterizing gene x gene and gene x environmental associations, and fostering clinicopathologic and psychosocial studies.